Radiation sterilization of medical devices

ABSTRACT

Disclosed herein is a method of radiation sterilizing a plurality of medical devices.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Disclosed herein are methods and apparatuses for sterilization ofmedical devices using radiation.

2. Description of the State of the Art

Disclosed herein are radially expandable endoprostheses adapted to beimplanted in a bodily lumen. An “endoprosthesis” corresponds to anartificial device that is placed inside the body. A “lumen” refers to acavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts or bar arms. The scaffolding canbe formed from wires, tubes, or sheets of material rolled into acylindrical shape. The scaffolding is designed so that the stent can beradially compressed (to allow crimping) and radially expanded (to allowdeployment). A conventional stent is allowed to expand and contractthrough movement of individual structural elements of a pattern withrespect to each other.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. The polymericscaffolding may also serve as a carrier of an active agent or drug.

After a stent is fabricated, a stent or a stent-catheter devicetypically undergoes sterilization to reduce the bioburden of the stentto an acceptable sterility assurance level (SAL). There are numerousmethods of sterilizing medical devices such as stents, the most commonbeing ethylene oxide treatment and treatment with ionization radiationsuch as electron beam (E-beam) and gamma radiation.

There is a desire to make E-beam sterilization commercially feasible forpolymeric stents. As medical devices increase in complexity,sterilization process technology becomes imperative. A commerciallyfeasible E-beam sterilization process that is compatible with existingE-beam facilities is desired. Also desired is a fixture apparatus havingthe capability of processing a large volume of medical devices in ashort period of time, robustness to human error, and reproducibility ofdose from device to device.

SUMMARY

Various embodiments of the present invention include a method ofradiation sterilizing a plurality of stent-catheter assemblies, themethod comprising: positioning a plurality of stent-catheter assemblieson a fixture, each of the stent catheter assemblies being arranged in aplanar configuration and disposed in corresponding planar packagessupported on the fixture, wherein the packages are stacked horizontallyon the fixture; and exposing the packages to an incoming radiation beam,the radiation beam being at an acute angle to the planes of the planarconfiguration of the assemblies, wherein the packages are arranged suchthat a front end of the stack faces the radiation beam and a back end ofthe stack faces away from the radiation beam.

Further embodiments of the present invention include a method ofradiation sterilizing a plurality of medical devices, the methodcomprising: positioning a plurality medical devices on a fixture; andexposing the devices to an incoming radiation beam through movement ofthe plurality of devices with respect to a radiation source, wherein thenumber of devices through which the radiation beam passes varies withthe movement, wherein a radiation shield is positioned such that avariation in radiation exposure among the medical devices from incomingor backscattered radiation is reduced.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an example of a stent.

FIG. 2 depicts a stent-catheter assembly.

FIG. 3( a) is a schematic illustration of a front view of a fixture forsupporting two packages, each package containing a stent-catheterassembly.

FIG. 3( b) depicts an overhead view of a fixture of FIG. 3( a).

FIG. 3( c) depicts a photograph an overhead view of a fixture supportingtwo chipboard boxes.

FIG. 4( a) depicts a schematic illustration of a front view of multiplepackages supported by a fixture, each package containing astent-catheter assembly.

FIG. 4( b) depicts an overhead view of the fixture of FIG. 4( a).

FIG. 4( c) depicts an overhead view of the fixture of FIG. 4( a)additionally including two radiation shields on the front and back ofthe fixture.

FIG. 4( d) is a schematic illustration of a front view of the fixture ofFIG. 4( c).

FIG. 5 depicts a photograph of multiple packages supported on a fixtureand two radiation shields on the front and the back of the fixture.

FIG. 6 depicts a depth to dose distribution curve illustrating therelationship between radiation exposure and depth of penetration of aradiation beam.

FIG. 7 depicts a package for a stent-catheter assembly, indicating threeareas of the package that are measured for radiation dose mapping of adevice.

FIG. 8 depicts a chart illustrating the radiation dose received bymultiple lots of chipboard boxes, each containing a stent-catheterassembly.

DETAILED DESCRIPTION OF THE INVENTION

Radiation sterilization is well known to those of ordinary skill in theart. Medical devices composed in whole or in part of polymers can besterilized by various kinds of radiation, including, but not limited to,electron beam (E-beam), gamma ray, ultraviolet, infra-red, ion beam,x-ray, and laser sterilization. Generally, it is desirable to increasethe throughput of sterilization processes to increase the manufacturingefficiency.

Various embodiments of the present invention relate to the sterilizationof multiple medical devices. Such medical devices include implantablemedical devices and delivery systems for such devices. The methodsdescribed herein may be applied generally to polymeric implantablemedical devices, such as for stents, in particular polymeric stents. Themethods reduce or narrow the range of radiation exposure from device todevice.

Therefore, each device may be irradiated within a specified or selectedrange. This is of particular importance for polymeric devices, sinceexposure to radiation above a specified range can cause undesirabledegradation of chemical and mechanical properties of a polymer. Themethods discussed herein reduce the likelihood of irradiation outside aspecified range, causing an undesirable increase in temperature and acorresponding undesirable degree of degradation.

The methods disclosed herein may be applied in combination with areduced temperature sterilization process in which a device is cooledbefore, during, and/or after sterilization. The reduced temperature canbe below ambient temperature during sterilization. The methods disclosedherein may be applied to a sterilization process using various kinds ofradiation.

Examples of implantable medical devices include, but are not limited to,self-expandable stents, balloon-expandable stents, stent-grafts, grafts(e.g., aortic grafts), artificial heart valves, cerebrospinal fluidshunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE andENDOTAK, available from Guidant Corporation, Santa Clara, Calif.). Theunderlying structure or substrate of the device can be of virtually anydesign.

FIG. 1 depicts an example of a stent 100. Stent 100 has a cylindricalshape and includes a pattern with a number of interconnecting structuralelements or struts 110. In general, a stent pattern may be designed sothat the stent can be radially compressed (crimped) and radiallyexpanded (to allow deployment). The stresses involved during compressionand expansion are generally distributed throughout various structuralelements of the stent pattern. The present invention is not limited tothe stent pattern depicted in FIG. 1.

A stent such as stent 100 may be fabricated from a polymeric tube or asheet by rolling and bonding the sheet to form a tube. A stent patternmay be formed on a polymeric tube by laser cutting a pattern on thetube. Representative examples of lasers that may be used include, butare not limited to, excimer, carbon dioxide, and YAG. In otherembodiments, chemical etching may be used to form a pattern on a tube.

Sterilization is typically performed on implantable medical devices,such as stents and catheters, to reduce the bioburden on the device.Bioburden refers generally to the number of microorganisms thatcontaminate an object. The degree of sterilization is typically measuredby a Sterility Assurance Level (“SAL”), referring to the probability ofa viable microorganism being present on a device unit aftersterilization. A sterilization dose can be determined by selecting adose that provides a required “SAL”. The required SAL for a device isdependent on the intended use of the device. For example, a device to beused in the body's fluid path is considered a Class III device. SALs forvarious medical devices can be found in materials from the Associationfor the Advancement of Medical Instrumentation (AAMI) in Arlington, Va.In one embodiment, the sterility assurance level for biodegradablestents is at a radiation dose from about 20 kGy to about 30 kGy.

A stent is typically sterilized after being mounted onto a deliverysystem or device, such as a catheter. Stents are also typicallysterilized, packaged, stored, and transported in a “ready to implant”configuration in which the stent is disposed at the distal end of acatheter. However, the methods described are not limited to sterilizinga mounted stent. FIG. 2 depicts a stent-catheter assembly 200 with astent 205 disposed on a distal end 210 of a catheter 215. Stent 205 canbe crimped over a balloon 220. Stent-catheter assembly 200 may bepackaged prior to or after radiation sterilization. Various embodimentsherein describe sterilization after stent-catheter assembly 200 ispackaged.

The embodiments described herein may be used for sterilizing variouskinds of devices, such as an implantable medical device, in particular astent-catheter assembly. In one embodiment, the device, as describedabove, can also be enclosed in a container or package. The container orpackage can include a sealable flexible metallic or plastic pouch thatis conventionally used for storage and shipping a stent-catheterassembly. Generally, the pouch protects the assembly from exposure toair, moisture, and light.

In an embodiment, a container or package of a stent-catheter assemblyincludes a chipboard box and a pouch that is disposed within the box.Typically, stent-catheter assemblies are sterilized after packaging bymethods such as E-beam sterilization. A packaged stent-catheter assemblyis supported on a fixture during sterilization. The fixture is typicallymoved on a conveyer arrangement past a radiation beam from a radiationsource in a manner that the radiation beam is directed onto thestent-catheter assembly. Alternatively, the radiation source can bemoved with respect to the fixture.

In a cold E-beam sterilization process, the stent-catheter assembly canbe cooled prior to and/or after sterilization. Additionally oralternatively, the temperature of the stent-catheter assembly can becontrolled at a reduced temperature during E-beam sterilization. Thestent-catheter assembly can be cooled to a reduced temperature below anambient temperature which can refer to a temperature between about15-30° C. In various embodiments, reduced temperature can be less than10° C., 0° C., −15° C., −25° C., −40° C., −70° C., −100° C., −150° C.,−200° C., −240° C., or less than −270° C. The stent-catheter assemblycan be cooled by various methods. For example, the cooling prior tosterilization can be performed by disposing the stent-catheter assemblyin a freezer for a time sufficient to cool the stent-catheter assemblyto a desired temperature.

FIG. 3( a) depicts a schematic illustration of a front view of a fixture310 supporting two packages 320, each containing a stent-catheterassembly 305 having a stent 330 and catheter 340. Packages 320 can be,for example, a chipboard box containing the stent-catheter assemblydisposed within a pouch. FIG. 3( b) depicts an overhead view of fixture310 of FIG. 3( a) containing packages 320.

In some embodiments, fixture 310 in FIG. 3( b) can be moved as shown byan arrow 325 past a stationary E-beam source that directs an E-beamperpendicular to the face of packages 320, the face being perpendicularto the plane of the page. As shown, a beam 345 is directed perpendicularto the faces of packages 320. The cross-section of the E-beam iscircular or generally circular in shape, as depicted by a pulse 342 ofan E-beam. In such embodiments, the E-beam is moved up and down as shownby an arrow 343 to irradiate fixture 310 and assemblies 305 along anaxis from position X to position Y. Thus, as fixture 310 is conveyed inthe direction shown by arrow 325, the entire fixture and assemblies 305can be irradiated. In some embodiments, the beam pulses up and down50-70 times, or more narrowly, 64 times a second.

FIG. 3( c) depicts a photograph of front view of fixture 310 supportingtwo chipboard boxes 320. Fixture 310 includes a metal plate 312 and asupport arm 315 that supports boxes 320. Behind chipboard boxes 320 is afoam slab 330. Behind foam slab 330 is support arm 315 of fixture 310that supports boxes 320. Chipboard boxes 320 are held onto support arm315 of fixture 310 by fasteners 340. Chipboard boxes can include astent-catheter assembly that is encased in a pouch (not shown).

In such an arrangement shown in FIGS. 3( a)-3(c), sufficientsterilization of the stent-catheter assembly 305 may require more thanone pass past the radiation source. Thus, stent-catheter assemblies 305can be irradiated with two passes, one pass for exposing one side of theassemblies, and the other pass for irradiating the other side of theassemblies.

With reference to FIG. 2, catheter 215 of stent-catheter assembly 200may be able to sustain radiation exposure to 50 kGy since theperformance of a catheter is less sensitive to radiation exposure.However, the performance of a stent, such as stent 205, is moresensitive to degradation by high radiation doses, in particular a stenthaving a polymer substrate and/or a polymer coating. High radiationdoses can adversely affect the chemical and mechanical properties of apolymer in the stent which can affect its therapeutic functions. Forexample, if a dose of 25 kGy is desired to be delivered to thestent-catheter assembly 200, two doses of 12.5 kGy are delivered to thedevice per pass in order to avoid over-exposing the stent to radiation.After irradiating the first side with 12.5 kGy of radiation by focusingthe E-beam directly on the package as described, the packages areflipped over to the other side, and irradiated with the remaining 12.5kGy of radiation.

Sterilization of two devices with two passes of radiation is timeconsuming and thus, reduces manufacturing efficiency and throughput. Anexemplary fixture may allow only two devices to be sterilized at a timeusing two passes, one for the front and the other for the back of thedevices. The devices can be cooled prior to the second irradiation stepto reduce or eliminate chemical and/or mechanical degradation of thepolymer of the stent caused by high radiation doses. Thus, sterilizationof two devices with two passes of radiation is even more time consumingwhen the devices must be cooled in between passes of radiation. In someembodiments, the cooling time can be several hours, for example, 12hours. Thus, cooling before the first pass can be 12 hours, coolingafter the first pass can be 12 hours, and cooling after the second passcan be 12 hours.

Additionally, it is desired to deliver a radiation dose to a device in apredictable, narrow range. In this way, reproducibility of the dosagefrom device to device may be achieved. As described above, one or twodevices may be irradiated during one pass of radiation. Such methods ofsterilization are limited in their capacity to deliver consistent doseswith a narrow range of radiation exposure from device to device.

In the embodiments described herein, multiple devices can be irradiatedand sufficiently sterilized with one pass of irradiation. In suchembodiments, the orientation of the devices on the fixture in relationto the beam (e.g., the orientation of the face of the package in FIG. 3(a) with respect to the beam) and the position of radiation shields onthe devices enable multiple devices (not just two) to be sterilized inone pass of radiation. Since multiple devices are sterilized in onepass, both processing time and throughput are increased compared to themethods illustrated in FIGS. 3( a)-(c). In addition, all of the deviceson the fixtures are irradiated substantially uniformly, such that therange of the radiation dose from device to device is very narrow andconsistent. Thus, reproducibility of radiation dose from device todevice is increased. By increasing reproducibility of radiation dose,fewer devices fall outside a desired SAL range. Also, sterilizingmultiple devices in one pass of radiation eliminates the need to coolthe devices between passes, further reducing manufacturing time andincreasing throughput.

Thus, the embodiments provide a method and apparatus for sterilizingmultiple devices at once. Multiple devices are positioned on a fixtureduring the single pass of radiation so that all of the devices areexposed to a radiation in such a way that the radiation dose from deviceto device falls within a narrow range. As a result, the methods andapparatus provide good reproducibility from device to device.

FIGS. 4( a)-(d) illustrate schematic embodiments of the presentinvention. FIG. 4( a) depicts a schematic illustration of multiplepackages 410 supported by a fixture 420, each package containing astent-catheter assembly 430 that includes a stent 440 mounted on acatheter 430. Packages 410 are stacked horizontally on fixture 420. FIG.4( b) depicts an overhead view of FIG. 4( b) of multiple packages 410supported by a fixture 420. Additionally, fixture 420 can include asupport element or side arm 427 that supports the stacked packages 410.Support element 427 can be metallic, for example, aluminum.

Packages 410 are staggered so that there is a non-overlapping portion452 between adjacent packages. As a result, packages 410 are positionedso that the face of the packages is at an acute angle, θ, relative tothe direction of the radiation beam 450. In one embodiment, packages 410are positioned such that θ is between 35-45 degrees, or more narrowly 45degrees. Fixture 420 in FIGS. 4( a) and 4(b) can be moved as shown by anarrow 425 past the stationary E-beam source that directs an E-beam at anangle θ to the face of packages 410. An arrow 450 shows the E-beamsource in FIG. 4( b). The arrangement depicted in FIGS. 4( a) and 4(b)allows sterilization of multiple devices in one pass. Because devicesare at an acute angle to beam 450 and staggered on fixture 420,radiation beam 450 penetrates several devices as fixture 420 moves asshown by arrow 425.

As shown in FIGS. 4( a)-(b), devices near a front end 465 of the stackof packages 410 have less shielding from radiation than those furtherbehind. As a result, the radiation exposure to the devices near thefront end of the stack can be different that those further behind thathave more shielding since radiation exposure varies with depth ofpenetration and density, as described below. The difference in shieldingcan result in a variation in radiation exposure due to incomingradiation from device to device.

Additionally, backscattering of radiation from metallic support elementor side arm 427 to packages 410 and devices contained within canincrease the radiation exposure to the devices. Backscatter ofradiation, such as electrons, is caused when the electrons hit a densematerial (such as a metallic fixture) and are reflected back. Theexposure due to backscatter can be desirable since the portions of thedevice closer to side arm 427 have reduced radiation exposure sinceradiation exposure varies with penetration depth, as described below.The backscatter of at least some radiation compensates for the reducedexposure. However, as shown in FIG. 4( a)-4(b), devices at a back end475 of the stack of packages 410 have more shielding from thebackscatter those closer to the front. The difference in shielding canresult in a variation in radiation exposure from device to device due tobackscatter.

In general, the thicker and/or denser a material is, the more it willscatter electrons, creating a “shadow” or lower dose area behind thedense material. In one embodiment, the densest part of fixture is placedtowards the back to prevent it from shadowing other parts of the device.For example, as pictured in FIG. 5, the densest part of fixture 420 isaluminum side arm 427, which is positioned such that it is behindassemblies 410 relative to beam 450.

FIG. 4( c) depicts an overhead view of a system similar to FIG. 4( a) ofa multitude of packages supported by a fixture 420, additionallyincluding two radiation shields 460 and 470 on at front end 465 and backend 475 of the stack of packages 410, respectively. FIG. 4( d) is aschematic illustration of a front view of the embodiment depicted inFIG. 4( c). In one embodiment, one or both of radiation shields 460 and470 are composed of foam.

FIG. 4( d) is a schematic illustration of a front view of the fixture ofFIG. 4( c). As depicted in FIGS. 4( c) and 4(d), radiation shields 460and 470 are strategically positioned on front end 465 and back end 475,respectively, of the stack of devices to reduce the radiation exposurevariation from device to device. Radiation shield 460 can reduce oreliminate the difference in radiation exposure between devices nearfront end 465 and those behind due to incoming radiation. Radiation beam450 can be modified prior to irradiating the devices located near thefront end 465 of the stack of devices on fixture 420, thereby providinggreater uniformity in radiation exposure to the devices. Radiationshield 460 can act effectively as a “dummy device.” In an embodiment,radiation shield 460 can provide shielding so that the devices near thefront end receive the same or similar exposure from incoming radiationas devices behind. Since radiation exposure varies with thickness anddensity, the thickness and density of the radiation barrier can beselected to obtain a desired exposure to devices.

Radiation shield 470 is positioned on the back end of fixture 420 toshield packages 410 from backscatter of the radiation from side arm 427.Radiation shield 470 can reduce or eliminate the difference in radiationexposure between devices near back end 475 and those behind due tobackscattering of radiation. Radiation backscattered from side arm 427can be modified prior to irradiating the devices located near back end475 of the stack of devices on fixture 420, thereby providing greateruniformity in radiation exposure to the devices. Radiation shield 475can also act effectively as a “dummy device.” In an embodiment,radiation shield 470 can provide shielding so that the devices near theback end receives the same or similar exposure from backscatteredradiation as devices at the front end. The thickness and density of theradiation barrier can be selected to obtain a desired exposure todevices.

Thus, one or more radiation shields can increase the uniformity of thedose received over the multitude of devices positioned on fixture 420.All devices on fixture 420 can be adequately sterilized during one passof radiation, which can increase throughput. Additionally, in a reducedtemperature sterilization process, the cooling step between passes iseliminated in a one pass process, which also reduces process time.

FIG. 5 depicts a photograph of a fixture with a multitude of deviceswith radiation shield 460 and radiation shield 470. An aluminum side arm427 behind the stacked packages 410 supports the packages. Metal sidearm 427 ensures that the packages are positioned on fixture 420 at anangle.

In one embodiment, as depicted in FIG. 5, fixture 420 contains between12-18 devices. In such embodiments, the radiation beam can penetratethrough one to 8 packages, or more narrowly, the radiation beam canpenetrate through five packages. It should be understood by thoseskilled in the art that fixture 420 can contain more or less devices,depending on the size of the device, the fixture, and the angle that thedevices are positioned on the fixture.

The dose is selected according to the devices to be sterilized. Forexample, a desired dose for a stent can be about 25 kGy. In oneembodiment a dose of incoming radiation can be set at 35-45 kGy, or morenarrowly, 40 kGy. The radiation dose received a stent can be lower thanthe incoming radiation due to modification of the radiation as it passesthrough packaging, devices, shielding, etc., as described below. Otherradiation doses can be used, depending on the device to be sterilized.

FIG. 6 depicts a depth dose distribution curve illustrating therelationship between radiation exposure and depth of penetration of theradiation beam for materials with two densities. The curve shows thedose versus the depth of a material that the electrons travel throughfor two densities. As depicted, the dose initially rises and then dropsoff. For example, if a device is irradiated with 40 kGy, the peak doseis at 44 kGy, and it eventually drops down to, for example, 25 kGy andfinally to 0 kGy upon further permeation through a material. As shown inFIG. 6, the curve is shifted to larger penetration as density isdecreased.

The general relationship in FIG. 6 can be used to design a fixture,arrangement of devices, and shields in a manner that devices received adesired radiation dose. The total exposure to a device can be fromincoming radiation and backscattered radiation. Thus, packages can bearranged, as described above, and the thickness and density of theshields can be selected to obtain a desired radiation exposure. Asdiscussed above, the shields can be selected to increase the uniformityof exposure from device to device. In alternate embodiments, the totalexposure can be due to incoming radiation, with no exposure due tobackscattering.

The curve in FIG. 6 can be manipulated by the radiation shields toobtain a desired dose level. The radiation shields having a certaindensity, like foam, are used to change the radiation dose to a desiredlevel in a specific depth of irradiated packages. Increasing the densityshifts the peak to a smaller depth, thus, larger depths have a smallerdose. By adding radiation shields at both ends of a fixture, as picturedin FIG. 5, the density dose curve advances to the descending portion ofthe curve prior to irradiating the fixtures, thereby reducing radiationabsorption of the device. In this way, devices on the ends of the stackare substantially consistent with the radiation absorption of the otherdevices that are shielded by other devices.

Thus, radiation shields can reduce the dose of radiation that thedevices are irradiated with by shifting the dose to depth curve. Sincethe packages are at an angle with respect to the beam, the radiationexposure varies at least as a function of “x” (FIG. 7) across the faceof the device, and more generally as a function of the “x” and “y”position on the face of the device. Thus, to have the same exposure foreach stent, the stents may be positioned to the same x position, or moregenerally at the same position on the face of the device. The positioncan be selected so that the stents receive a desired radiation exposure.

As depicted in FIG. 7, a stent-catheter assembly 710 with a stent 725disposed on a catheter 720 can be inside a storage package 715. Devicesare positioned on fixture such that stents are at an angle φ. In oneembodiment, devices are positioned such that each stent is positioned atthe same angle φ in each package to increase the uniformity of exposureto the stent from device to device. In one embodiment, stent 725 may bepositioned in a package 715 on a fixture such that stent 725 is at a 7o'clock (φ=216°) position when viewing stent 710 from the front of thefixture. Stents may be positioned within package 715 on the fixture inother angles, such that it is between 1 and 3 (φ=36-108°), or morenarrowly, at a 2 o'clock (φ=72°) position when viewing stent 725 fromthe front of fixture.

At various parts of the stent, radiation dose requirements may differ.However, when sterilizing multiple stent-catheter assemblies, it ispreferable that the radiation dose at the stent not vary substantiallyfrom stent to stent since E-beam exposure affects properties of amaterial. The radiation dose received by a stent should be within anarrow range from stent to stent. At the catheter 720, a tolerance for avariation in radiation exposure is higher. The radiation exposure, forexample, can be between at 20-50 kGy because the catheter is more robustthan the stent for example. In contrast, the performance of a balloon,over which a stent is disposed, is much more vulnerable to degradation,thus it is desirable for its exposure to be at less than 40 kGy.Performance of stent 710 and balloon 725 are more sensitive to changesin properties, and thus, radiation exposure. Performance of catheter 720is less sensitive to various properties, so a greater variation ofradiation exposure for the catheter is more tolerable.

Dose mapping may be used to monitor the range of radiation dose receivedby selected portions of irradiated devices. Dose mapping refers tomeasuring radiation exposure at specific areas of an irradiated packageand device within the package. FIG. 7 depicts three areas A, B, and Cwhere the radiation may be measured.

FIG. 8 depicts a chart illustrating the radiation dose received bymultiple lots of chipboard boxes, each containing a stent-catheterassembly. The system for sterilization is as depicted in FIG. 5. Eachlot corresponds to 15 chipboard boxes that are exposed to one pass ofradiation. The radiation dose corresponds to the radiation exposure at aparticular region of each stent in each lot. The radiation dose receivedby a particular area of the stents that are packaged and irradiated arecompared to multiple lots as illustrated by the graph. As indicated, thespread of radiation ranges from 24.3 to 26.8, with the frequency ofdoses being much higher in the 24.7 to 26.2 range. Thus, most devicesare of a very narrow range of about 24 to 26 KGy. Providing a narrowdose range prevents irradiating devices outside their required SAL,outside of a defined tolerance, or both. The likelihood of exposing apar of a device to radiation outside a desired SAL is reduced.

In one embodiment, devices are irradiated at a reduced temperature and“Targeted Dose” process. The device may be cooled prior to, during, orafter sterilization. The stent can be cooled in a variety of ways,including, but not limited to, cooling the stent in a freezer, blowing acold gas on the stent, placing the stent in proximity to a cold mediumsuch as ice, dry ice, freezable gel, liquid nitrogen, etc.

The storage package for the implantable medical device, such as a stent,can be designed in any convenient form, shape and size that permits theeffective enclosure of a stent contained therein. For example, aflexible pouch made from a polymer, glass, ceramic, metallic substance,or a combination thereof. Package can be made from metal, foam, plasticetc. For example, a material with micro-voids, such as foam, orparticles, can scatter E-beam radiation which results in the more evendistribution. “Foam” can refer to a polymer foam, for example,polystyrene foam such as Styrofoam from Dow Chemical Company, Midland,Mich. Thus, the package material can also be made of a material thatdistributes radiation more uniformly such as foam.

The package may be compact and shaped so as to minimize storage spaceoccupied by the package. For example, without limitation, the packagecan be in the shape of a tube, box or a pouch. In one embodiment, thepackage can have a rectangular cross-section with a width between 8 inand 12 in and a length between 10 in and 13 in. Also, depending on thetypes of substance(s) used to construct the package, the package can beof various degrees of rigidity or flexibility.

Such packages can be stored individually or stored together with otherpackaged stents. For example, a pouch can be disposed in a box, such aschipboard box. The chipboard box can then be stored individually oralong with a number of similar or identical packages including stents.

The package may be made of a metallic substance, the package for examplecan be formed of a metallic film. Suitable examples of films include,but are not limited to, gold, platinum, platinum/iridium alloy,tantalum, palladium, chromium, and aluminum. Suitable materials for thepackage may also include oxides of the above-mentioned metals, forexample, aluminum oxide. Medical storage packages may be obtained from,for example, Oliver Devices Company of Grand Rapids, Mich.

A polymer for use in fabricating an implantable medical device, such asa stent, can be biostable, bioabsorbable, biodegradable or bioerodable.Biostable refers to polymers that are not biodegradable. The termsbiodegradable, bioabsorbable, and bioerodable are used interchangeablyand refer to polymers that are capable of being completely degradedand/or eroded when exposed to bodily fluids such as blood and can begradually resorbed, absorbed and/or eliminated by the body. Theprocesses of breaking down and absorption of the polymer can be causedby, for example, hydrolysis and metabolic processes. For stents madefrom a biodegradable polymer, the stent is intended to remain in thebody for a duration of time until its intended function of, for example,maintaining vascular patency and/or drug delivery is accomplished.

The device may also be made of a metallic material or an alloy such as,but not limited to, a biodegradable metal.

The device may also include a drug or active agent that can include, butis not limited to, any substance capable of exerting a therapeutic,prophylactic, or diagnostic effect. The drugs for use in the implantablemedical device, such as a stent or non-load bearing scaffoldingstructure may be of any or a combination of a therapeutic, prophylactic,or diagnostic agents. The drug can be incorporated in a polymersubstrate or in a coating on the substrate that includes the drug withina polymer carrier.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects.

EXAMPLES

Three experiments were performed to map the dose distribution on abiodegradable stent and delivery system using a fixture as depicted inFIG. 4( b). For each of the experiments, 15 packages containing stentswere stacked onto the aluminum fixture such that the packages wereangled 45° to the trajectory of the radiation beam. The delivered doseat a particular region of the stent in each package was measured.

In the first experiment, no radiation shield of foam was positioned atthe front end or back end of the fixture. The delivered dose rangeabsorbed by the stents ranged from 15.88 to 20.96 kGy, or a ratio of1:32.

In the second experiment, a radiation shield of foam was positioned atthe front end of the fixture. The results indicated a reduction in thedose spread absorbed by the stents ranged from 22.49 to 25.48 kGy, or aratio of 1:14. It is believed that the backscatter from the aluminumfixture at the back end was contributing to scatter, and thus, thespread.

In the third experiment, a radiation shield of foam was added to boththe front end and the back end of the fixture. In other words, aradiation shield was positioned on both ends of the stack of devices. Onthe back end of the fixture, the spread of radiation absorbed by thestents ranged from 23.89 to 26.6 kGy, or a ratio of 1:11. Thisexperiment was repeated to confirm the results, having a ratio of 1:05.Thus, a radiation shield positioned at both ends of the stack of deviceson the fixture provided the narrowest spread of radiation dose among thedevices positioned on the fixture.

1. A method of radiation sterilizing a plurality of stent-catheterassemblies, the method comprising: Positioning a plurality ofstent-catheter assemblies on a fixture, each of the stent catheterassemblies being arranged in a planar configuration and disposed incorresponding planar packaged supported on the fixture, wherein thepackages are stacked horizontally on the fixture, and wherein the stentsof the assemblies are positioned at a position in each package such thatthe stents are exposed to the same or substantially the same radiation;and Exposing the packages to an incoming radiation beam, the radiationbeam being at an acute angle to the planes of the planar configurationof the assemblies, wherein the packages are arranged such that a frontend of the stack faces the radiation beam and a back end of the stackfaces away from the radiation beam, wherein a radiation shield ispositioned at the front end of the stack to reduce radiation exposure toselected assemblies adjacent the front end from the incoming radiation.2. The method according to claim 1, wherein the radiation beam comprisesan e-beam radiation beam.
 3. The method according to claim 1, whereinthe planar packages in the stack are staggered along an edge of thestack facing the radiation beam.
 4. The method according to claim 1,wherein radiation shield is positioned and the properties of theradiation shield are selected such that variation in radiation exposureto the selected assemblies from incoming radiation and the otherassemblies in the stack is reduced, substantially eliminated, oreliminated.
 5. The method according to claim 1, wherein the stents ofthe assemblies are positioned at a position in each package such thatthe stents are exposed to the same or substantially the same radiation.6. The method according to claim 1, wherein each of the stent catheterassemblies are arranged in a coiled configuration.
 7. The methodaccording to claim 1, wherein the incoming radiation is 35-45 KGy andthe stent in each of the assemblies is positioned at 36°-108° in thecoiled configuration.
 8. The method according to claim 1, wherein theacute angle is 35°-45°.
 9. The method according to claim 1, whereinexposing the packages to a radiation beam comprises movement of thefixture with respect to the incoming radiation beam.
 10. The methodaccording to claim 9, wherein the assemblies are sufficiently sterilizedafter one movement of the fixture with respect to the incoming radiationbeam.
 11. The method according to claim 1, wherein the assemblies arecooled prior to, during or after positioning the assemblies on thefixture.
 12. A method of radiation sterilizing a plurality ofstent-catheter assemblies, the method comprising: Positioning aplurality of stent-catheter assemblies on a fixture, each of the stentcatheter assemblies being arranged in a planar configuration anddisposed in corresponding planar packages supported on the fixture,wherein the packaged are stacked horizontally on the fixture, andwherein the stents of the assemblies are positioned in each package suchthat the stents are exposed to the same or substantially the sameradiation; and Exposing the packages to an incoming radiation beam, theradiation beam being at an acute angle to the planes of the planarconfiguration of the assemblies, wherein the packages are arranged suchthat a front end of the stack faces the radiation beam and a back end ofthe stack faces away from the radiation beam, wherein a radiation shieldis positioned at the back end of the stack to reduce backscatter ofradiation from a support element of the fixture to selected assembliesadjacent the back end.
 13. The method according to claim 12, wherein theradiation shield is positioned and the properties of the radiationshield are selected such that a variation in radiation exposure frombackscattered radiation to the selected assemblies and the otherassemblies in the stack is reduced, substantially eliminated, oreliminated.
 14. A method of radiation sterilizing a plurality of medicaldevices, the method comprising: positioning a plurality of medicaldevices on a fixture; and exposing the devices to an incoming radiationbeam through movement of the plurality of devices with respect to aradiation source, wherein the number of devices through which theradiation beam passes varies with the movement, wherein a radiationshield is positioned such that a variation in radiation exposure amongthe medical devices from incoming or backscattered radiation is reduced.15. The method according to claim 14, wherein the radiation shield ispositioned between a support element of the fixture and selecteddevices, the radiation shield reducing radiation exposure frombackscattering from the support element to the selected devices.
 16. Themethod according to claim 14, wherein the radiation shield is positionedbetween the incoming radiation beam and selected devices, the radiationshield modifying radiation exposure from the incoming radiation to theselected devices.
 17. The method according to claim 14, wherein theradiation shield comprises foam.
 18. The method according to claim 14,wherein the devices are cooled prior to, during or after positioning thedevices on the fixture.
 19. The method according to claim 14, wherein aselected portion of each of the devices are positioned such that theselected portion of each of the devices is exposed to the same orsubstantially the same radiation.
 20. A method of radiation sterilizinga plurality of medical devices, the method comprising: only one coolingstep, wherein in the only cooling step a plurality of medical devicesare cooled; positioning the plurality of medical devices on a fixture;positioning a radiation shield relative to the medical devices such thata variation in radiation exposure among the medical devices fromincoming or backscattered radiation is reduced; and only one sterilizingstep, wherein in the only sterilizing step there is only one pass of aradiation beam to expose the plurality of medical devices to radiation.21. The method according to claim 20, wherein the radiation shield ispositioned between a support element of the fixture and selecteddevices, the radiation shield reducing radiation exposure frombackscattering from the support element to the selected devices.
 22. Themethod according to claim 20, wherein the radiation shield is positionedbetween the incoming radiation beam and selected devices, the radiationshield modifying radiation exposure from the incoming radiation to theselected devices.
 23. The method according to claim 20, wherein theradiation shield comprises foam.
 24. A method of sterilizing a stack ofpackages of medical devices, the method comprising: placing a stack ofpackages of medical devices horizontally on a fixture having a supportelement, the step of positioning the stack including: placing the stackbetween a radiation source and the support element of the fixture,staggering the stack of packages horizontally so that there is anon-overlapping portion between adjacent packages, and positioning thestack of packages so that faces of the packages are at an acute anglerelative to a radiation beam from the radiation source; positioning aradiation shield relative to the stack of packages such that a variationin radiation exposure among the medical devices from incoming orbackscattered radiation is reduced; and exposing the packages to anincoming radiation beam.
 25. The method of claim 24, wherein eachmedical device is placed in the same horizontal and vertical positionswithin the package.
 26. The method of claim 25, wherein the step ofpositioning a radiation shield includes positioning a radiation shieldat the front end of the stack to reduce radiation exposure to one ormore packages in the front end from incoming radiation.
 27. The methodof claim 26, wherein the step of positioning a radiation shield includespositioning a radiation shield at the back end of the stack to reducebackscatter of radiation from the support element of the fixture to oneor more packages in the back end of the stack.
 28. The method of claim27, wherein the thickness and/or density of at least one of theradiation shields are varied to obtain a desired exposure to thepackages.
 29. The method of claim 24, wherein the step of positioning aradiation shield includes positioning a radiation shield at the frontend of the stack to reduce radiation exposure to one or more packages inthe front end from incoming radiation.
 30. The method of claim 29,wherein the step of positioning a radiation shield includes positioninga radiation shield at the back end of the stack to reduce backscatter ofradiation from the support element of the fixture to one or morepackages in the back end of the stack.
 31. The method of claim 30,wherein the thickness and/or density of at least one of the radiationshields are varied to obtain a desired exposure to the packages.
 32. Themethod of claim 31, wherein the packages are exposed to the incomingradiation beam to irradiate the packages substantially uniformly. 33.The method of claim 24, wherein the step of positioning a radiationshield includes positioning a radiation shield at the back end of thestack to reduce backscatter of radiation from the support element of thefixture to one or more packages in the back end of the stack.
 34. Themethod of claim 33, wherein the thickness and/or density of theradiation shield is varied to obtain a desired exposure to the packages.35. The method of claim 34, wherein the packages are exposed to theincoming radiation beam to irradiate the packages substantiallyuniformly.
 36. The method of claim 24, wherein the packages are exposedto the incoming radiation beam to irradiate the packages substantiallyuniformly.
 37. A method of sterilizing a stack of packages of medicaldevices, the method comprising: Placing a stack of packages of medicaldevices horizontally on a fixture having a support element, the step ofpositioning the stack including: Placing the stack between a radiationsource and the support element of the fixture, Staggering the stack ofpackages horizontally so that there is a non-overlapping portion betweenadjacent packages, and Positioning the stack of packages so that facesof the packages are at an acute angle relative to a radiation beam fromthe radiation source, Wherein each medical device is not placed in themiddle of the package, and wherein each medical device is placed in thesame horizontal and vertical positions within the package; Exposing thepackages to an incoming radiation beam, and positioning a radiationshield relative to the stack of packages such that a variation inradiation exposure among the medical devices from incoming orbackscattered radiation is reduced.
 38. The method of claim 37, whereinthe step of positioning a radiation shield includes positioning aradiation shield at the front end of the stack to reduce radiationexposure to one or more packages in the front end from incomingradiation.
 39. The method of claim 38, wherein the step of positioning aradiation shield includes positioning a radiation shield at the back endof the stack to reduce backscatter of radiation from the support elementof the fixture to one or more packages in the back end of the stack. 40.The method of claim 39, wherein the thickness and/or density of at leastone of the radiation shields are varied to obtain a desired exposure tothe packages.
 41. The method of claim 37, wherein the step ofpositioning a radiation shield includes positioning a radiation shieldat the back end of the stack to reduce backscatter of radiation from thesupport element of the fixture to one or more packages in the back endof the stack.
 42. The method of claim 41, wherein the thickness and/ordensity of at least one of the radiation shields are varied to obtain adesired exposure to the packages.
 43. A method of sterilizing a stack ofpackages of stents, the method comprising: placing a stack of packagesof stents horizontally on a fixture having a support element, the stepof positioning the stack including: placing the stack between aradiation source and the support element of the fixture, staggering thestack of packages horizontally so that there is a non-overlappingportion between adjacent packages, and positioning the stack of packagesso that faces of the packages are at an acute angle relative to aradiation beam from the radiation source, wherein each stent is notplaced in the middle of each package, and wherein each stent is placedin the same horizontal position within the package, each stent is placedin the same vertical position within the package, or each stent isplaced in the same horizontal and vertical positions within the package;positioning a radiation shield relative to the stack of packages suchthat a variation in radiation exposure among the stents from incoming orbackscattered radiation is reduced, wherein the step of positioning aradiation shield includes positioning a radiation shield at the frontend of the stack to reduce radiation exposure to one or more packages inthe front end from incoming radiation, and positioning a radiationshield at the back end of the stack to reduce backscatter of radiationfrom the support element of the fixture to one or more packages in theback end of the stack, wherein the thickness and/or density of at leastone of the radiation shields are varied to obtain a desired exposure tothe packages; and exposing the packages to an incoming radiation beam,wherein the packages are irradiated substantially uniformly.
 44. Amethod of sterilizing a stack of packages of stents, the methodcomprising: placing a stack of packages of stents horizontally on afixture having a support element, the step of positioning the stackincluding: placing the stack between a radiation source and the supportelement of the fixture, staggering the stack of packages horizontally sothat there is a non-overlapping portion between adjacent packages, andpositioning the stack of packages so that faces of the packages are atan acute angle relative to a radiation beam from the radiation source;positioning a radiation shield relative to the stack of packages suchthat a variation in radiation exposure among the stents from incoming orbackscattered radiation is reduced, wherein the step of positioning aradiation shield includes positioning a radiation shield at the frontend of the stack to reduce radiation exposure to one or more packages inthe front end from incoming radiation, and positioning a radiationshield at the back end of the stack to reduce backscatter of radiationfrom the support element of the fixture to one or more packages in theback end of the stack, wherein the thickness and/or density of at leastone of the radiation shields are varied to obtain a desired exposure tothe packages; and exposing the packages to an incoming radiation beam,wherein the packages are irradiated substantially uniformly.
 45. Amethod of sterilizing a stack of packages of stents, the methodcomprising: placing a stack of packages of stents horizontally on afixture having a support element, the step of positioning the stackincluding: placing the stack between a radiation source and the supportelement of the fixture, staggering the stack of packages horizontally sothat there is a non-overlapping portion between adjacent packages, andpositioning the stack of packages so that faces of the packages are atan acute angle relative to a radiation beam from the radiation source,wherein each stent is not placed in the middle of each package, andwherein each stent is placed in the same horizontal and verticalpositions within the package; positioning a radiation shield relative tothe stack of packages such that a variation in radiation exposure amongthe stents from incoming or backscattered radiation is reduced, whereinthe step of positioning a radiation shield includes positioning aradiation shield at the front end of the stack to reduce radiationexposure to one or more packages in the front end from incomingradiation, and positioning a radiation shield at the back end of thestack to reduce backscatter of radiation from the support element of thefixture to one or more packages in the back end of the stack, whereinthe thickness and/or density of at least one of the radiation shieldsare varied to obtain a desired exposure to the packages; and exposingthe packages to an incoming radiation beam, wherein the packages areirradiated substantially uniformly.